High fat diet increases melanoma cell growth in the bone marrow by inducing osteopontin and interleukin 6

Abstract

The impact of metabolic stress induced by obesity on the bone marrow melanoma niche is largely unknown. Here we employed diet induced obese mice model, where mice received high-fat (HFD) or normal diet (ND) for 6 weeks before challenge with B16F10 melanoma cells. Tumor size, bone loss and osteoclasts numbers were assessed histologically in the tibial bones. For defining the molecular pathway, osteopontin knock-out mice, interleukin 6 neutralizing antibody or Janus kinase 2 inhibition were carried out in the same model. Mechanistic studies such as adipocyte-melanoma co-cultures for defining adipocyte induced changes of tumor cell proliferation and expression profiles were also performed. As results, HFD enhanced melanoma burden in bone by increasing tumor area and osteoclast numbers. This process was associated with higher numbers of bone marrow adipocytes expressing IL-6 in direct vicinity to tumor cells. Inhibition of IL-6 or of downstream JAK2 blocked HFD-induced tumor progression. Furthermore, the phenotypic changes of melanoma cells triggered macrophage and osteoclast accumulation accompanied by increased osteopontin expression. Osteopontin triggered osteoclastogenesis and also exerted a positive feedback loop to tumor cells, which was abrogated in its absence. Metabolic stress by HFD promotes melanoma growth in the bone marrow by an increase in bone marrow adipocytes and IL-6-JAK2-osteopontin mediated activation of tumor cells and osteoclast differentiation.

Adipogenic niches for melanoma cell colonization and growth in bone marrow

“…Mouse BM mesenchymal stem cells (BM-MSC) were prepared as previously described. 11,20 BM-MSC or the murine adipocyte cell line (14F1.1 cells, kindly provided by Prof. Dov Zipori of the Weizmann Institute of Science, Rehovot, Israel) were differentiated into BM adipocytes as previously reported. 11 As shown in Figure 2a, BM-MSC cells or 14F1.1 cells were pre-treated with adipogenic cocktail (adipo-coc: 5 μg/ml insulin, 0.5 mM 3-isobutyl-1-methylxanthine, 1 μM dexamethasone) for 2 days.…”

“…11,20 BM-MSC or the murine adipocyte cell line (14F1.1 cells, kindly provided by Prof. Dov Zipori of the Weizmann Institute of Science, Rehovot, Israel) were differentiated into BM adipocytes as previously reported. 11 As shown in Figure 2a, BM-MSC cells or 14F1.1 cells were pre-treated with adipogenic cocktail (adipo-coc: 5 μg/ml insulin, 0.5 mM 3-isobutyl-1-methylxanthine, 1 μM dexamethasone) for 2 days. Then, the tumor-conditioned medium (TCM) was collected from the B16-F10 cells, which were cultured in FBS-free medium for 24-48 h and mixed with adipo-coc (40%) as the medium used for the adipocyte differentiation assay.…”

“…9 A higher incidence of bone metastasis has been observed in elderly patients than in younger patients, 10 and this might indicate a role for BM adipocytes in bone metastasis. In recent studies, BM adipocytes that were induced by obesity were shown to promote cancer cell growth in the bone-tumor niche 11,12 and to enhance osteoclastogenesis via chemokine (C-X-C motif) ligand-1/-2 (CXCL-1/-2) and osteopontin (OPN). 11,13 In addition, adipocytes that synthesize cytokine-like proteins called adipokines, which include leptin, interleukin 6 (IL-6), insulin-like growth factor 1 (IGF-1), and CXCL-1/-2, are also potentially involved in metastasis.…”

“…In recent studies, BM adipocytes that were induced by obesity were shown to promote cancer cell growth in the bone-tumor niche 11,12 and to enhance osteoclastogenesis via chemokine (C-X-C motif) ligand-1/-2 (CXCL-1/-2) and osteopontin (OPN). 11,13 In addition, adipocytes that synthesize cytokine-like proteins called adipokines, which include leptin, interleukin 6 (IL-6), insulin-like growth factor 1 (IGF-1), and CXCL-1/-2, are also potentially involved in metastasis. 14 Furthermore, BM adipocytes negatively regulate the hematopoietic stem cell (HSC) pool, 15,16 which is shared with metastasizing cancer cells.…”

Roles of omental and bone marrow adipocytes in tumor biology

“…(C-X-C motif) ligand (CXCL)1 and CXCL2, chemokines produced by BMA, enhance osteoclastogenesis in metastatic prostate cancer and prolong tumour cell survival [96]. Upregulated expression of IL-6 in malignant melanoma cells increased osteoclastogenesis, which could induce the proliferation of tumour cells [97]. CXCL1 and CXCL2 also participate in immune modulation, acting as chemoattractants for macrophages, neutrophils, and CD11b+Gr1+ cells [98,99].…”